Alcohol dependence is a highly prevalent and debilitating disorder that exhibits relapse rates over 80% despite current treatment efforts. Human alcoholics as well as animal models of dependence exhibit chronic alterations in gene expression that underlie neuroplastic alterations within the reward circuitry of the brain. The mechanisms that lead to chronic disruption of gene expression profiles remain unclear. Alterations in epigenetic modifications to DNA and histone tails have been shown to be associated with alcohol dependence. These epigenetic changes could underlie chronic alterations in gene expression, cellular dysfunction, and ultimately contribute to alcohol seeking behaviors. However, the epigenetic regulatory pathways upstream of these changes remain to be explored. Transcriptomic analysis identified two epigenetic enzymes that are dysregulated in key brain reward regions of a well validated post-dependent (PD) rodent model of alcohol dependence, PR domain containing 2 (PRDM2) and lysine-specific demethylase 6B (KDM6B). These enzymes have both been shown to modulate NF-?B-mediated inflammatory responses in cultured macrophages and microglia. Viral-mediated in vivo shRNA knockdown of PRDM2 in the prefrontal cortex increased alcohol seeking behaviors. The known roles of PRDM2 and KDM6B in immune cell responses are consistent with evidence that inflammatory signaling pathways are critical for the development of uncontrolled drinking behaviors. A combination of behavioral, epigenomic, transcriptomic, and histological approaches will be used to test whether PRDM2 and KDM6B mediate epigenetic control of inflammation-associated transcriptional changes that underlie alcohol dependence. The expression of PRDM2 and KDM6B will first be manipulated using viral vectors delivered to brain reward regions in order to characterize their effects on alcohol-seeking behaviors compared to assessments of general locomotion, anxiety, and natural reward. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), will be used to identify the gene loci subject to dynamic regulation by PRDM2 and KDM6B in alcohol dependent rats. [The effects of PRDM2 and KDM6B are on microglial activation, NF-?B activation, and inflammatory cytokine expression will be functionally assessed using histological, pharmacological, and biochemical analysis in PD rats.] These studies have potential to identify novel epigenetic mechanisms that underlie long-term transcriptional dysregulation, inflammatory signaling, and maladaptive drinking behaviors in alcohol dependence. Given the emerging interest in targeting epigenetic enzymes using small molecule therapies for complex disease, the identification of epigenetic signaling networks that are dysregulated in alcohol dependence could lead to novel therapeutic approaches for this intractable disorder.